Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating

Stacey L. Kirkpatrick, Lisa R. Goldberg, Neema Yazdani, R. Keith Babbs, Jiayi Wu, Eric R. Reed, David F. Jenkins, Amanda F. Bolgioni, Kelsey I. Landaverde, Kimberly P. Luttik, Karen S. Mitchell, Vivek Kumar, W. Evan Johnson, Megan K. Mulligan, Pietro Cottone, Camron D. Bryant

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions. Methods We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2 cross to identify quantitative trait loci associated with binge eating. We used gene targeting to validate candidate genetic factors. Finally, we used transcriptome analysis of the striatum via messenger RNA sequencing to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment. Results C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant quantitative trait locus on chromosome 11 (logarithm of the odds = 7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms morphine addiction and retrograde endocannabinoid signaling, whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression. Conclusions We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.

Original languageEnglish (US)
Pages (from-to)757-769
Number of pages13
JournalBiological Psychiatry
Volume81
Issue number9
DOIs
StatePublished - May 1 2017

Fingerprint

Bulimia
Proteins
Quantitative Trait Loci
Gene Expression Profiling
Inbred C57BL Mouse
Transcriptome
Morphine Dependence
RNA Sequence Analysis
Endocannabinoids
Chromosomes, Human, Pair 11
Gene Targeting
Genome-Wide Association Study
Oligodendroglia
Missense Mutation
Knockout Mice
Substance-Related Disorders
Down-Regulation
Genome
Food
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Biological Psychiatry

Cite this

Kirkpatrick, S. L., Goldberg, L. R., Yazdani, N., Babbs, R. K., Wu, J., Reed, E. R., ... Bryant, C. D. (2017). Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating. Biological Psychiatry, 81(9), 757-769. https://doi.org/10.1016/j.biopsych.2016.10.021

Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating. / Kirkpatrick, Stacey L.; Goldberg, Lisa R.; Yazdani, Neema; Babbs, R. Keith; Wu, Jiayi; Reed, Eric R.; Jenkins, David F.; Bolgioni, Amanda F.; Landaverde, Kelsey I.; Luttik, Kimberly P.; Mitchell, Karen S.; Kumar, Vivek; Johnson, W. Evan; Mulligan, Megan K.; Cottone, Pietro; Bryant, Camron D.

In: Biological Psychiatry, Vol. 81, No. 9, 01.05.2017, p. 757-769.

Research output: Contribution to journalArticle

Kirkpatrick, SL, Goldberg, LR, Yazdani, N, Babbs, RK, Wu, J, Reed, ER, Jenkins, DF, Bolgioni, AF, Landaverde, KI, Luttik, KP, Mitchell, KS, Kumar, V, Johnson, WE, Mulligan, MK, Cottone, P & Bryant, CD 2017, 'Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating', Biological Psychiatry, vol. 81, no. 9, pp. 757-769. https://doi.org/10.1016/j.biopsych.2016.10.021
Kirkpatrick, Stacey L. ; Goldberg, Lisa R. ; Yazdani, Neema ; Babbs, R. Keith ; Wu, Jiayi ; Reed, Eric R. ; Jenkins, David F. ; Bolgioni, Amanda F. ; Landaverde, Kelsey I. ; Luttik, Kimberly P. ; Mitchell, Karen S. ; Kumar, Vivek ; Johnson, W. Evan ; Mulligan, Megan K. ; Cottone, Pietro ; Bryant, Camron D. / Cytoplasmic FMR1-Interacting Protein 2 Is a Major Genetic Factor Underlying Binge Eating. In: Biological Psychiatry. 2017 ; Vol. 81, No. 9. pp. 757-769.
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AU - Kirkpatrick, Stacey L.

AU - Goldberg, Lisa R.

AU - Yazdani, Neema

AU - Babbs, R. Keith

AU - Wu, Jiayi

AU - Reed, Eric R.

AU - Jenkins, David F.

AU - Bolgioni, Amanda F.

AU - Landaverde, Kelsey I.

AU - Luttik, Kimberly P.

AU - Mitchell, Karen S.

AU - Kumar, Vivek

AU - Johnson, W. Evan

AU - Mulligan, Megan K.

AU - Cottone, Pietro

AU - Bryant, Camron D.

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N2 - Background Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions. Methods We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2 cross to identify quantitative trait loci associated with binge eating. We used gene targeting to validate candidate genetic factors. Finally, we used transcriptome analysis of the striatum via messenger RNA sequencing to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment. Results C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant quantitative trait locus on chromosome 11 (logarithm of the odds = 7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms morphine addiction and retrograde endocannabinoid signaling, whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression. Conclusions We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.

AB - Background Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions. Methods We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2 cross to identify quantitative trait loci associated with binge eating. We used gene targeting to validate candidate genetic factors. Finally, we used transcriptome analysis of the striatum via messenger RNA sequencing to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment. Results C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant quantitative trait locus on chromosome 11 (logarithm of the odds = 7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms morphine addiction and retrograde endocannabinoid signaling, whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression. Conclusions We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.

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